Embolism protection devices

ABSTRACT

Embolism protection devices can be formed with a biocompatible expandable polymer that can expand upon release within a patient&#39;s vessel. Upon release, the structure can be configured to filter flow through the vessel. The material of the embolism protection devices can release one or more biologically active agents, such as a thrombolitic agent, including, for example, tPA. Alternatively or additionally, the embolism protection device can be connected to a tether that elutes one or more biologically active agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/414,909, filed Apr. 16, 2003, now issued U.S. Pat. No. 7,303,575 toOgle, entitled “Embolism Protection Devices, incorporated herein byreference, which claims priority to U.S. Provisional Patent ApplicationSer. No. 60/400,341, filed Aug. 1, 2002, to Ogle, entitled “EmbolismProtection Device,” incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to devices for preventing blockage of passagewaysin a patient's body. In particular, the invention relates to devicesplaced within a vessel, such as a blood vessel or a urinary vessel, totrap occlusions, such as emboli, for their dissolution or removal, aswell as related methods.

BACKGROUND OF THE INVENTION

An embolus can be any particle comprising a foreign or native material,which enters the vascular system with potential to cause occlusion ofblood flow. Emboli can be formed from aggregated fibrin, red bloodcells, collagen, cholesterol, plaque, fat, calcified plaque, bubbles,arterial tissue, and/or other miscellaneous fragments. Emboli range insize from 0.01 cubic millimeters (mm³) to 12.5 mm³ (with an approximatemean of 0.80 mm³). Emboli characterization is described furtherdescribed in reference 1. (1) While some references are cited explicitlyin the text, other references are cited in a list at the end of thespecification. References listed at the end of the specification arecited with a number of the reference in parentheses. These referencesare incorporated by reference in their entirety as well as specificallyfor the particular principle being referenced.

Cardiac Surgery

Each year there are approximately 800,000 cardiac surgical cases whichinvolve cardiopulmonary bypass (CPB) worldwide. (2) Of these cardiacsurgical cases, approximately 48,000 suffer stroke and nearly 300,000experience some neurocognitive disturbance. (3) This is a significantclinical problem. These complications are due in large measure toCPB-generated emboli. The average number of emboli measured by TransCranial Doppler (TCD) in patients undergoing cardiopulmonary bypass is183 (range 3-947). (2) The majority of emboli end up in the very distalcerebral tree, the terminal arterioles and capillaries causingmicroinfarctions, (i.e., loss of blood to surrounding tissue). (4)Pathological evaluation of affected tissues reveals sausage-shapedarterial dilatations known as SCADs. Cerebral microinfarctions can causeconfusion, disturbances of speech, paralysis, visual disturbances,balance disturbances and other neurological deviations. (5) Theseimpairments are frequently short term but can be permanent.

Whether long term or short term, neurocognitive disturbances translateinto significant patient care spending. An estimated $750 milliondollars is spent annually on hospital care for CPB patients and anadditional $500 million on long-term hospice care. (2) The average stayfor CPB patients without adverse cerebral outcomes is 8.6 days, whilepatients with severe adverse outcomes stay an average of 55.8 days. (3and 6) Estimating the average hospital day care cost at $1500/day,extended stays due to embolic events translate on average into anadditional $60,000 per patient. While daunting, this figure still failsto include the social and financial burden placed on family members uponhospital release. In sum, surgically triggered embolic events cause highrates of clinically observed neurological disturbances, decreasedquality of life and increased patient care spending.

Cardiac surgical procedures have been correlated directly withneurological injury and stroke due in large measure to the formation ofemboli. Emboli can be generated by surgical maneuvers such ascannulation, aortic manipulation, clamping and unclamping. In fact, bysome estimates, 60% of the total emboli can be associated with clampmanipulation alone. The average number of emboli measured by TransCranial Doppler (TCD) in patients undergoing coronary bypass is 135(range 0-1377), and in patients undergoing vascular surgery, the averagenumber increases to 1030 (range 18 to 5890). The majority of the emboliend up in the very distal cerebral tree, the terminal arterioles andcapillaries causing microinfarcts, (i.e., loss of blood to surroundingtissue).

Furthermore, mortality increased from 7.4% in patients without adversecerebral outcomes to 30.4% in patients who did have adverse cerebraloutcomes. A study conducted in Sweden reviewed 7,000 open heartprocedures. Their results with respect to incidence of symptoms as apercentage of all cases are as follows: disturbance of consciousnessincluding slow awakening (1.8%), confusion (5.3%), disturbances ofspeech (1.3%), paresis (2.0%), visual disturbances (1.0%),balance/coordination disturbances (2.3%), seizures (0.2%) and otherneurological deviations (1.8%).

Vascular Surgery

Emboli formation can also create problems in the realm of vasculardisease, though in these instances the clinical outcome can be pulmonaryembolism (PE). Approximately 600,000 people in the United States sufferfrom venous thrombi, which could result in a lung embolus. Mortalityassociated with untreated PE is approximately 30%. (7) While secondaryto cardiac surgery, this area represents a Significant clinicalindication.

Cardiology and Endovascular Intervention

Other procedures that can result in emboli include, for example,coronary, carotid, and peripheral interventions. (8) In these cases,particulate matter, including, for example, plaque, debris and thrombus,can form emboli distal to the site of intervention. As a result, bloodflow to the distal vascular bed is diminished and periproceduralend-organ ischemia and infarction can result. Distal embolization oflarge particles produced at the time of such interventions as ballooninflation or stent deployment may obstruct large, epicardial vessels,and smaller particles (as little as 15-100 microns) can causemicroinfarcts and/or myocardial infarctions and left ventriculardysfunction. (8) Myocardial infarction refers to the death of a sectionof myocardium or middle layer of the heart muscle. Myocardial infarctioncan result from at least partial blockage of the coronary artery or itsbranches. Blockage of capillaries associated with the coronary arteriescan result in corresponding microinfarctions/microinfarcs.

Urology and Gastroenterology

Blockage of other body vessels can occur. For example, kidney stones areone of the most painful of the urologic disorders. Kidney stones alsorepresent one of the most common disorders of the urinary tract; it isestimated that more than 1 million cases were diagnosed in 1996. It hasalso estimated 10 percent of people in the United States will have akidney stone at some point in their lives. While most kidney stones passout of the body without any intervention, stones that cause lastingsymptoms or other complications require removal. Thus, like the otheremboli generated in vascular system, urology could benefit from adevices to remove and resorb calculi in the urinary tract. This calculiis composed of calcium oxalate. Since it is a relatively hard substance,it can cause great pain as it passes through the urinary tract. Suchremoval is often necessary in cases of obstruction, i.e. embolism.

Emboli and Infection

When foreign material in the stream of flow causes turbulence or lowflow, it has been shown that this increases infection rates. Thrombusnot only generates emboli, but also increases the risk of infection. (9)Likewise kidney stones can create additional risk for infection.

It is evident that a wide variety of embolic events cause high rates ofclinically observed symptoms, decreased quality of life and increasedpatient care spending.

SUMMARY OF THE INVENTION

In a first aspect, the invention pertains to an embolism protectiondevice comprising a biocompatible expandable polymer. The expandablepolymer can expand upon release within a patient's vessel into astructure configured to filter flow through the vessel. Correspondingmethods relate to delivering an embolism protection device into apatient's vessel.

In another aspect, the invention pertains to an embolism protectiondevice comprising a biocompatible resorbable polymer forming a porousstructure having a configuration to filter flow through a patient'svessel.

In an additional aspect, the invention pertains to an embolismprotection device comprising a polymer forming a porous structure and abiologically active agent that elutes from the device when the device isin contact with flow within a patient's vessel. The porous structure hasa configuration to filter flow through the patient's vessel.

Moreover, the invention pertains to an embolism protection devicecomprising a first section and a compositionally distinct secondsection. The first section has a different average composition from theaverage composition of the second section. Also, the first section andthe second section are configured for placement within a patient'svessel with a substantial fraction of flow passing sequentially throughthe first section and the second section.

Furthermore, the invention pertains to a system for providing protectionfrom emboli comprising an embolic protection device and a delivery tool.The delivery tool is configured for releasing the embolism protectiondevice into a vessel from the catheter. The embolism protection devicecomprises a biocompatible expandable polymer.

In addition, the invention pertains to a method for reducing oreliminating adverse effects of an embolus, the method comprisesdelivering an embolism protection device and administering abiologically active agent. The delivering of the embolism protectiondevice can be performed within a vessel of a patient with the devicebeing tethered with a tether such that the embolism protection devicefilters flow within the vessel. The administering of the biologicallyactive agent can be performed through the tether.

In an additional aspect, the invention pertains to an embolismprotection device comprising a plurality of fibers having surfacecapillaries. The fibers are bound within a structure and have a deployedconfiguration that fills the lumen of a vessel having a diametercorresponding to that of a human vessel. The fibers can include one ormore surface capillary channels. The capillary channels within a singlefiber are substantially parallel to each other, if there are multiplesurface capillary channels, and substantially parallel to the length ofthe fiber. The capillary channels can have an open groove along at leastabout 20% of their length and generally along from about 90% to 100% oftheir length.

In a further aspect, the invention pertains to a system for trappingemboli comprising a delivery tool comprising a tether and an embolismprotection device attached to the tether. The embolism protection devicecomprises a fiber with surface capillaries with a size suitable forplacement within a human vessel.

In another aspect, the invention pertains to a method for trappingemboli, the method comprising placing a fiber within a patient's vesselwherein the fibers have surface capillaries.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view of an embolism protection device withina patient's vessel with the left view showing the deployment of thedevice from a deployment apparatus and the right view showing the devicefollowing deployment.

FIG. 2 is a schematic perspective view of an alternative embodiment ofan embolism protection device within a patient's vessel with the leftview showing the deployment of the device from a deployment apparatusand the right view showing the device following deployment.

FIG. 3 is a schematic perspective view of another alternative embodimentof an embolism protection device within a patient's vessel with the leftview showing the deployment of the device from a deployment apparatusand the right view showing the device following deployment.

FIG. 4 is a schematic side view of another alternative embodiment of anembolism protection device within a patient's vessel with the left viewshowing the deployment of the device from a deployment apparatus and theright view showing the device following deployment.

FIG. 5A is a schematic side view of an alternative embodiment of anembolism protection device within a patient's vessel followingdeployment.

FIG. 5B is an end on view of the device of FIG. 5A viewed along line B-Bof FIG. 5A.

FIG. 6A is a schematic side view of an alternative embodiment of anembolism protection device within a patient's vessel with the left viewshowing the deployment of the device from a deployment apparatus and theright view showing the device following deployment.

FIG. 6B is an end on view of the device of FIG. 6A viewed along line B-Bof FIG. 6A.

FIG. 7A is a schematic side view of an alternative embodiment of anembolism protection device within a patient's vessel with the left viewshowing the deployment of the device from a deployment apparatus and theright view showing the device following deployment.

FIG. 7B is an end on view of the device of FIG. 7A viewed along line B-Bof FIG. 7A.

FIG. 8A is a schematic perspective view of an alternative embodiment ofan embolism protection device within a patient's vessel with the leftview showing the deployment of the device from a deployment apparatusand the right view showing the device following deployment.

FIG. 8B is an end on view of the device of FIG. 8A viewed along line B-Bof FIG. 8A.

FIG. 9 is a schematic side view of an alternative embodiment of anembolism protection device with a tether to facilitate removal within apatient's vessel with the left view showing the deployment of the devicefrom a deployment apparatus and the right view showing the devicefollowing deployment.

FIG. 10 is a schematic side view showing the use of the tether to removethe device of FIG. 9.

FIG. 11 is a schematic side view of an embolism protection device withtwo portions having different properties.

FIG. 12 is a schematic view showing possible positioning of embolismprotection devices within an aorta and corresponding branch vessels.

FIG. 13 is a schematic view of an embolism protection device associatedwith an aortic cannula during cross-clamp bypass.

FIG. 14 is a schematic view of the embolism protection device of FIG. 13following removal of the cross-clamp.

FIG. 15 is a schematic view of an embolism protection device deployed ina coronary artery.

FIG. 16 is a schematic view of an embolism protection device in thepulmonary artery.

FIG. 17 is a schematic view of an embolism protection devices positionedin blood vessels in a patient's leg and arm.

FIG. 18A is (left) a schematic side view of a two-component embolismprotection device downstream from a plaque deposit and (right) anenlarged cross sectional view of an embodiment of a surface capillaryfiber.

FIG. 18B is a schematic view of the device of FIG. 18A followingdeployment of a stent at the plaque deposit.

FIG. 18C is a schematic view of the removal of one component of theembolism protection device of FIG. 18A.

FIG. 19 is a side view of an embolism protection device associated witha guide-wire through which a biologically active agent is delivered atone or more of locations A, B and C.

FIG. 20 is a side view of a gripper device to facilitate removal of anembolism protection device.

FIG. 21 is a photomicrographs of a PET fiber.

FIG. 22 is a photomicrograph of a PET fiber with grafted with apolyacrylamide hydrogel.

FIG. 23 is a plot of the standard curve for a tPA ELISA.

FIG. 24 is a plot of the elution of tPA from a hydrogel as a function oftime, which provides information on the release kinetics.

FIG. 25 is a diagram showing an in vitro flow loop.

FIG. 26 is schematic side view of a composite embolism protection devicewith two materials prior to expansion.

FIG. 27 is a schematic side view of the embolism protection device ofFIG. 26 following expansion.

FIG. 28 is a side view of an embodiment of a mount for supporting anembolism protection device within the flow loop of FIG. 25.

FIG. 29A is a micrograph of a fibrin emboli recovered from an embolismprotection device that released tPA, at a magnification of 200×.

FIG. 29B is a micrograph of the fibrin emboli in FIG. 29A at amagnification of 400×.

FIG. 29C is a micrograph of a fibrin emboli recovered from an embolismprotection device that did not released tPA, at a magnification of 200×.

FIG. 29D is a micrograph of the fibrin emboli in FIG. 29C at amagnification of 400×.

DESCRIPTION OF THE INVENTION

Improved medical devices to capture and/or remove/dissolve emboli andsimilar particles can incorporate a polymer that expands in an aqueousenvironment of the body. The emboli have the potential to occludevessels to form an embolism in a patient. Suitable polymers include, forexample, hydrogels and memory polymers that resume a memory shape uponexposure to a stimulus such as heating to body temperature. In someembodiments, the embolism protection device comprises a blend ofpolymers, such as a structural polymer that provides a framework for thedevice and a hydrogel. The blend of polymers can be in the form of agraft copolymer or the like. The devices can further comprise abioactive agent, such as an agent that is effective to dissolve theemboli. Generally, the embolism protection device is removed followingan appropriate period of time to effectively remove any emboli withinthe device. The embolism protection device generally is used to controlemboli following a medical procedure.

An embolus as used herein refers broadly to a particle, besides livingcells, in a vessel within a mammal having a diameter of at least about 5microns. For this determination, the diameter is considered the largestdistance between two points on the surface of the particle. Thus, emboliwould encompass emboli within the blood as well as kidney stones and thelike. Vascular emboli are thought to be composed almost exclusively ofclotted blood. Arterial emboli generated in aortic surgery orendovascular intervention can be composed of other components, but it isgenerally believed that they nearly all contain some component offibrin. See, for example, Reichenspumer et al., “Particulate embolicapture by an inter-aortic filter device during cardiac surgery,” J.Thorac. Cardiovasc. Surg. 119(2):233-241 (February 2000), Harringer,“Capture of particulate emboli during cardiac procedures in which aorticcross-clamp is used,” Ann. Thorac. Surg. 119(2):701119-23 (February2000) and Webb, “Retrieval and analysis of particulate debris aftersaphenous vein graft intervention,” J. American College Cardiol.34(2):468-475 (1999), all three of which are incorporated herein byreference. In some embodiments, embolism protection devices, describedherein, can protect the patients in at least one of three ways: first byfiltering emboli, second by dissolving entrapped emboli and third bybathing the distal myocardial bed or other down flow portion of a vesselwith a beneficial bioactive agent, such as an embolism dissolvingcompound, for example, tissue plasminogen activator (tPA), to helpresolve emboli which have become impacted there.

The embolism protection device can be delivered, for example, out of amedical implement (catheter or syringe) into the desired vessel, such asa vascular vessel. In some embodiments, the material of the device canswell/dilate quickly upon exposure to the aqueous environment of apatient's body to circumferentially encompass/fill the vessel. Theexpansion of the device can anchor the device within the vessel due tocontact with the vessel wall. In some embodiments, the device can havethe flexibility to conform to the geometry of the vessel. The materialsand structure of the device can be selected to have porosity that wouldallow blood elements, such as white blood cells (about 7-20 microns),red blood cells (8-9 microns) and platelets (2-4 microns), yet collectsemboli. In contrast, emboli generally range in size with diameters fromabout 20 microns to about 3.5 mm, in some embodiments from about 45microns to about 1000 microns and in further embodiments from about 50microns to 200 microns. A person of ordinary skill in the art willrecognize that additional ranges of emboli within the explicit rangesare contemplated and are within the present disclosure. Thus, in someembodiments of interest, the trapping of emboli with a size larger thanabout 45 microns to about 50 microns would be beneficial.

In some embodiments of particular interest, an embolism protectiondevice can comprise a polymeric substrate (media, sponge), especially anexpandable polymer, such as a swelling polymer, a memory polymer or acompressed polymer. Specifically, in some embodiments, the embolismprotection devices described herein generally comprise a swellingpolymer that expands, generally spontaneously, upon contact with anaqueous solution, such as blood or other body fluids. Swelling isconsidered broadly in terms of significant changes in dimension due toan absorption or other intake of fluid/liquid into the structure of thematerial, such as with a sponge, a hydrogel or the like. Hydrogels aregenerally hydrophylic polymers that are nevertheless not soluble inaqueous solutions. Generally, hydrogels are crosslinked to prevent themfrom being soluble. While they do not dissolve, the hydrogels swell withaqueous solution when in contact with the solution due to thehydrophylic nature of the polymer. In additional or alternativeembodiments, an expandable polymer can comprises a memory polymer thatresumes a memory shape upon exposure to a stimulus, such as exposure tobody temperature. In other embodiments, the expandable polymer cancomprise a compressible polymer that expands upon release of a confiningforce such as the confinement provided by a sheath or the like.Furthermore, the embolism protection device can comprise additionalpolymers and/or other material to introduce desired properties to thedevice.

Thus, in some embodiments of interest, the devices have a component ofan expandable polymer to fill the inner luminal space of the vessel. Inaddition, copolymers and/or polymer blends can be used in which one ormore expandable polymers is combined with other monomer and/or polymermoieties to combine the properties of the different elements. Forexample, block copolymers, such as graft copolymers, can be used tocombine polymer units into a combined material that incorporatesproperties of the respective polymers. Some embodiments of swellingpolymers include, for example, hydrogels, which can expand large amountsupon contact with aqueous solutions. Various hydrogels suitable formedical applications are known in the art, and particular embodimentsare described further below.

Additional polymers, such as polyesters, polyurethanes, modifiedpolyurethanes, and polycarbonates, within a copolymer or a polymer blendcan provide mechanical strength to the composite material. The embolismprotection device can comprise one or more additional materials, asdesired, to provide particular structural or functional features. Forexample, the outer surface can comprise a material, such as an adhesiveor a fabric that expands with the material but contributes to anchoringof the device to the wall of the vessel. Some embodiments could containmultiple materials for modifying the composition and/or the structure,as desired.

With appropriate sizing, the embolism protection device can be appliedto any size vessel of a patient. The patient can be any animal,generally a mammal, with particular interest in humans, farm animals andother domestic animals. The devices generally have an ability to conformto irregularly shaped portions of a vessel. Thus, this invention couldbe used for a vascular surgery to prevent a clot, which could causeparalysis, amputation, surgical vascular intervention, otherneurological impairment or death. Due to complications from emboli, suchas a thrombus, there is a significant clinical need for an effectiveprotection from emboli and resulting embolisms. For example, significantpotential applications pertain to coronary intervention following AcuteMyocardial Infarct (AMI). These cases can represent 25% of all coronaryinterventions (as reported at GW Stone Lennox Hill Hospital) due inlarge part to the commonly thrombus-laden lesions found in AMI patients.Due to the flexibility of some embodiments of devices described hereinand the speed at which they can be applied, an embolism protectiondevice can be applied in a wide range of circumstances. In cases such asa broken hip, deployment of the embolism protection device could bepreformed as an emergency procedure to prevent clot formation forpatient's with pro thrombotic disease which are known to clot. While thefocus of the discussion herein focuses on material within blood vesselsand the like, there is also interest in and prevention of occlusion ofother biological vessels in a patient. In particular, the embolismprotection device can be used in other vessels of a patient, such asurinary tract vessels.

In some embodiments, a biologically active agent can be released by wayof the embolism protection device. For example, the biologically activeagent can be released from a reservoir within the embolism protectiondevice either quickly and/or in a gradual fashion. Additionally oralternatively, the embolism protection device can be connected during aprocedure to an external source of biologically active agent that isreleased in a desired dose at or near the embolism protection device.For embodiments in which the embolism protection device comprises areservoir of biologically active agents, the embolism protection devicecan also elute a biologically active agent from one or more materials,which could aid in neurological/vascular disease prevention associatedwith surgical. In some embodiments, the reservoir of biologically activeagent is physically trapped within the material such that it is releasedquickly by expansion of the material upon delivery of the device. Inother embodiments, the biologically active agent is eluted gradually bydiffusion out from the material in which it is embedded or releasedgradually by degradation of the material. In some embodiments, theembolism protection device remains connected to a wire followingdelivery in which the wire has a small inner lumen through which thebiologically active agent is delivered. The delivery through the wirecan be at a controlled time and rate, for example, with a syringe,peristaltic pump or the like.

Some embodiments have one or more emboli dissolving agents releasedlocally to reduce the emboli. These agents can be thrombolytic agentssuch as tissue plasminogen activator (tPA) or urokinase, or the agentscan release mild acid (possibly along with a neutralizing base, such asbicarbonate) or anti-calcification enzymes such as osteopontin to resorbcalcific plaque. In other embodiments, the devices can release O₂ and/orsugars to nourish the patient's brain cells. In other embodiments, thedevice can release vasodilators such as NO or heparin to increase theavailable O₂ transport. In other embodiments, the device can releasegrowth factor, which could improve healing or create new vessels. Infurther embodiments, the device can release viral vectors, whichtransfected the surrounding cell to up regulate the release apolypeptide compound for extended therapy (e.g., tPA). Specifically, forprotein/polypeptide based agents, the delivery of a gene (nucleic acid)encoding the agent in a vector, such as a viral vector, to promote invivo expression of the protein is an alternative to the delivery of theprotein itself. Delivery of vectors for desired polypeptides isdescribed further below. The device similarly can be designed to releasea plurality of these agents.

In some embodiments, the material of the device or a portion thereof canbe selected to slowly resorb over time. In these embodiments, the devicecan be left within the patient rather than being removed. In someembodiments, even if a portion of the resorbable material were todislodge from the aggregated material of the device, the resorbablematerial can still have the same porosity thus be able to filter whileproviding flow further up the vascular tree. Resorbable materials withinthe embolism protection device could be tuned to dissolve over a timerange from a very short time to a very long time after surgery, asdesired. In some embodiments; an imaging approach can determine thepresence of calcified plaque trapped within the embolism protectiondevice, which would then be removed surgically. In some embodiments astring/tether can be attached to the device for extraction of thedevice. This attachment can act to reduce the luminal size of the deviceupon extraction for some embodiments of the device. In some embodiments,an extraction device, such as a gripper or the like, can be used tofacilitate the removal of the embolism protection device by physicallycompressing the embolism protection device.

Thus, the embolism protection devices described herein can be effectiveto reduce or eliminate damage resulting from emboli in circumstances inwhich potential damage may be indicated by the performance of particularmedical procedure, from the identification of diseases and/or byinjuries to the patient. The material properties of the device providegreat flexibility in the design of the device with respect to differentpotential ways of handling the emboli. Through the use ofswellable/expandable polymers, the devices can be very versatile withrespect to convenience of delivery, conformability to a wide range ofvessels and uniform performance in a range of environments. By combiningbiologically active agents with the devices, the improved structuralfeatures can be combined with the ability to deliver treatments to alocalized environment.

Embolism Protection Device Structures

The embolism protection devices can have various sizes and shapes bothwith respect to the exterior surface before and after deployment andwith respect to the arrangement of the materials through the crosssection of the structure. The shape of the exterior of the device caninfluence the nature of the deployment, removal and/or performance ofthe device. The nature of the arrangement of the material across thedevice generally is formulated to be consistent with the maintenance offlow through the device while capturing emboli over an appropriate sizesuch that they do not flow past the device.

With respect to the shape of the exterior of the device, this shape canbe, for example, generally spherical, cylindrical, concave, or saddleshaped. A generally spherical or other shaped device may neverthelesshave a roughly irregular surface contour about an average overall shape,which can orient and adjust to the vessel inside wall upon expansion.Some representative examples are provided below. Any particular devicegenerally can conform to the size and shape of the inside of the vessel.While the particular device size depends on the size of the particularvessel, an embolism protection device following expansion within thevessel of a human patient general can have a diameter perpendicular tothe flow direction from about 50 microns to about 35 millimeters (mm),in additional embodiments from about 100 microns to about 9 mm and infurther embodiments, from about 500 microns to about 7 mm. A person ofordinary skill in the art will recognize that additional ranges ofdevice diameters within the explicit ranges are contemplated and arewithin the present disclosure.

The texture of the outer surface can reflect the structure of theinterior of the device, or the texture of the exterior of the device canbe altered to provide a particular surface texture. For example, thesurface of the device may be porous to reflect the porosity of thedevice generally to the flow. Alternatively, the surface can be treatedto alter the texture and/or covered with a material, such as a fabric,to present an alternative surface contacting the inner surface of thevessel. For example, a fabric cover over the exterior can improve thegripping of the vessels interior surface without damaging the vesselwall. Suitable biocompatible fabrics can be used, such as those formedfrom polyesters.

Once the embolism protection device is positioned within a vessel,appropriate flow should be maintained through the device while emboliare trapped. Thus, with respect to the flow direction, the device hascontrolled porosity. This controlled porosity can be established by thenature of the material and/or by the particular structure. Specifically,the polymer density and composition within the device can lead to adistribution of pores such that desired flow is provided while emboliare trapped by the lack of pores with a diameter large enough for theemboli to pass. In some embodiments, the device comprises a composite oftwo structures/materials with different pore sizes from each other. Forexample, the device can comprise a first material with an average poresize following expansion of the device between about 150 microns and 300microns to be positioned approximately downstream and a second materialwith an average pore size of about 50 microns to be positionedapproximately upstream. Alternatively or additionally, the polymers canbe specifically arranged to have a structure that directly leads to poresizes with desired sizes one the device expands within the vessel. Forexample, the polymer can form tubes with selected diameters that orientalong flow direction of the vessel, as described further below.

In general, the desired filtering properties and corresponding averagepore sizes and pore size distributions of an embolism protection devicemay depend on the particular location of the particular vessel in whichit is delivered. However, for many applications it can be desirable toblock the flow of a substantial majority of particulates with a diameterof at least about 0.2 mm while allowing the flow of a substantialmajority of particulates with a diameter of no more than about 0.001 mm,and in other embodiments, to block the flow of a substantial majority ofparticulates with a diameter of at least about 0.1 mm while allowing theflow of a substantial majority of particulates with a diameter of nomore than about 0.01 mm. A person of ordinary skill in the art willrecognize that additional ranges of filtering ability within theexplicit ranges are contemplated and are within the present disclosure.A substantial majority of particulates can be considered to be at leastabout 99 percent.

In some embodiments, it is desirable to remove the embolism protectiondevice at some period of time following deployment. Since the embolismprotection device expands to contact the interior of the vessel walls,it may be desirable to introduce structures that facilitate the removalof the device. For example, the device can comprise one or more tubes,sheaths, rigid extensions, wires, strings, filaments, tethers or thelike appropriately positioned for extracting the device. In someembodiments, the strings are placed such that pulling on the stringtends to contract the device to reduce or eliminate friction on thevessel wall. For example, the strings can be positioned at or near theouter edge of the device that contacts the vessel wall such that pullingon the string tends to pull the exterior of the device toward the centerof the vessel. Tethers and the like also can be useful to maintain anembolism protection device at a delivered position within a vessel.Thus, with a tether or guide wire to maintain the position of theembolism protection device against flow within the vessel, the devicemay or may not exert significant force against the inner wall of thevessel.

In addition, an extractor device can be positioned with a catheter orthe like near the embolism protection device. For example, the extractorcan comprise a gripping element that grips the device to reduce itsdimensions by physical force such that the embolism protection devicecan be removed through a catheter or the like. A specific embodiment ofa gripping device is described in the examples. Similarly, an extractorcan comprise a sheath or the like. The embolism protection device can betapered such that an end of the expanded device fits within the sheath.Then, pulling the device relative to the sheath, such as using a tetheror the like, can compress the device within the sheath for removal ofthe device within the sheath from the patient. Similarly, the device canbe twisted in a cork-screw type fashion to decrease the diameter of thedevice due to the torque and the compressible nature of the polymers.Similar approaches can be used for placement of the devices within asheath for delivery of the device. For embodiments of embolismprotection devices intended for removal from the patient, it may bedesirable to have a smaller porosity toward the vessel wall relative tothe porosity away from the vessel wall to reduce the possibility ofemboli escaping from the device during the removal of the device fromthe patient. A specific embodiment with this structure is describedfurther in the examples below.

Referring to FIG. 1, the left view displays an amorphous, generallyspherical embolism protection device 100 adjacent a catheter 102 withina vessel 104. The right hand view in FIG. 1 shows device 100 followingexpansion to fill the lumen of vessel 104. The arrow indicates atemporal advance over which device 100 swells across the lumen of vessel104. In this embodiment, device 100 has a random array of fibrouspolymer forming the interior of the device 100. In an alternativeembodiment, embolism protection device 110 has a cylindrical shape witha random interior polymer structure 112, as shown in FIG. 2. In thisembodiment, device 110 has an outer surface covered with a fabric 114excluding the flow ends through which the flow of the vessel passes.Referring to further alternative embodiment in FIG. 3, embolismprotection device 120 has a generally cylindrical shape with a polymermatrix 122 that is approximately arranged on a grid. The outer surfaceof the cylinder is covered with fabric 124 with the ends of the cylinderexposed, i.e., free of the fabric. If fabric 124 has a sufficiently openweave, the fabric may also cover the ends of the cylindrical structure.

As noted above, the embolism protection device can have a concave shapealong the direction of the flow. Referring to FIG. 4, embolismprotection device 130 has a generally bullet shape with the fluid floworiented along arrow 132. Device 130 may or may not have a hollowed outinterior along the concave surface. A saddle shaped embolism protectiondevice 140 is shown in FIGS. 5A and 5B. In the side view of FIG. 5A, thedirection of fluid flow is indicated by arrow 142. Device 140 has aconvex central portion 144 with an outer collection portion 146. In thisembodiment, device 140 has a cuff 148, which for example can be formedfrom rolled fabric or other polymer material, for contacting the wall ofvessel 104. Force from the flow tends to force emboli 150 away fromcentral portion 144 toward outer portion 146. An end view is shown inFIG. 5B. A bioactive agent, such as an thrombolytic agent, can belocated at outer portion 146 for concentration at the location ofemboli.

Referring to FIGS. 6A and 6B, embolism protection device 154 has anexpandable outer section 156 that forms a hole 158 in the center uponexpansion. This embodiment generally is intended to trap a largerembolism. While it is possible to design device 154 to provide some flowthrough outer section 156, generally this device is removed shortlyfollowing the capture of a larger embolism since flow can besignificantly reduced due to the embolism. A variation on thisembodiment is shown in FIGS. 7A and 7B. In this embodiment, embolismprotection device 160 has polymer elements 162 that extend through acentral core 164 within an outer ring 166. Polymer elements 162 create afilter that traps larger elements from the flow. Polymer elements may ormay not swell upon contact with an aqueous solution, although outer ring166 swell to expand to the wall of vessel 104.

Referring to FIGS. 8A and 8B, embolism protection device 170 has aplurality of tubular shaped passages 172 along the length of thegenerally cylindrical device. The outer cylindrical surface 174 may ormay not be covered in a fabric. Furthermore, the tubular shaped passages172 can be formed from a collection of polymer tubes assembled togetherto form the structure or from tubular openings through a polymer matrix.

As noted above, an embolism protection device as described herein cancomprise a tether or the like to facilitate removal of the device aftersufficient time to protect against emboli. Referring to FIG. 9, embolismprotection device 180 comprises two strings 182, 184 that tether device180, although a single string or greater than two strings can be used.Device 180 is shown in an unexpanded configuration in the left wide ofFIG. 9 and in its expanded form in the right side of FIG. 9. Byproviding two strings, pulling on the strings tends to draw the stringstogether to contract the device if the strings are in a spaced apartattachment on the device. As shown in FIG. 10, tension on strings 182,184, as indicated by arrow 186, is resulting in contraction in diameterof device 180 and corresponding movement from right to left. Otherconfigurations of strings can be used to tether an embolism protectiondevice to facilitate removal and to contract the device, which maydepend on the particular shape and structure of the device.

The embolism protection devices can comprise a composite of differentstructures, materials and/or bioactive agents. In particular, in theseembodiments, the embolism protection device can have identifiableportions that are compositionally distinct with respect to the averagecomposition within the portion. In some embodiments, the portions arepositioned such that the flow or a substantial fraction of the flowpasses sequentially through one section followed by another section. Insuch a configuration, generally at least about 25% of the flow volumeand in other embodiments at least about 80% of the flow volume flowsequentially through the first portion followed by the second portion. Aperson of ordinary skill in the art will recognize that additionalranges of flow within the explicit ranges are contemplated and arewithin the present disclosure.

For example, as shown in FIG. 11, embolism protection device 190comprises an up-flow portion 192 and a down-flow portion 194, where flowthrough the vessel is indicated with arrow 196. In some embodiments,up-flow portion 192 can elute, for example, a weak acid that tends todissolve at least some emboli, while down-flow portion 194 can comprisea buffer that neutralizes the weak acid as it flows downstream.

In some embodiments, up-flow portion 192 and down-flow portion 194 canbe separable. Thus, for example, up-flow portion 192 can provide a mesh,a sponge-like material and/or another porous material across the flow tocollect emboli for subsequent removal. Down-flow portion 194 can be atubular structure that does not significantly alter the flow, but elutesa bioactive agent, such as tPA and/or NO. Since the portions separate,up-flow portion 192 can be taken from the vessel to remove the trappedemboli while down-flow portion remains in the vessel to elute beneficialagents. In alternative embodiments, the positions of the two portionscan be reversed with respect to the flow and the portion to be removed,i.e., the down-stream portion can be removed to leave the up-streamportion. In variations on this embodiment, the down-flow portion canalso trap emboli. Thus, following the removal of the up-flow portion,the down-flow portion can be effective to trap emboli. The down-flowportion can be formed from a bioresorbable material such that itdissolves at a desired rate.

The structures in FIGS. 1-11 are representative structures for theembolism protection device. Additional structures can be formed based onthe disclosure herein.

In some embodiments, the embolism protection devices can be distributedalong with other components that can be used along with otherinstruments that facilitate the use of the embolism protection device.For example, an embolism protection device can be distributed along withdelivery tools, retraction devices, tools for the delivery ofbiologically active agents, instructions and other suitable tools.Suitable delivery tools include, for example, sheaths and/or cannulainto which the embolism protection device can be placed for deliveryalong with other catheter components that can facilitate the delivery ofthe device. Suitable retraction devices that facilitate the removal ofthe embolism protection device are described herein, which can bedistributed with the embolism protection device. For the delivery of abiologically active agent along with the embolism protection device, aguide-wire with a hollow core and/or a cannulated syringe can bedistributed with the embolism protection device. The cannulated syringecan be connected to the guide-wire for the delivery of a biologicallyactive agent in the vicinity of the embolism protection device withinthe patient's vessel. The guide-wire may or may not be associated withthe embolism protection device as a tether. In addition, the embolismprotection device can be distributed with instructions, which can taketo form of written instructions and/or electronic copies, including, forexample, a direction to a suitable web site. The commonly distributedelements can be distributed in one or more containers, for example, as akit. While the embolism protection device generally is disposablefollowing removal from the patient, the other individual elementsdistributed with the embolism protection device may or may not bereusable following sterilization.

Materials

The embolism protection device can be fabricated from biocompatiblematerials, which can be delivered in vivo with limited vessel trauma,and, in some embodiments, can possess the ability to break downentrapped emboli. Some materials comprise a matrix, which can be capablein some embodiments of expanding upon delivery, capable of withstandingin vivo pressures to minimize movement and/or capable of deliveringthrombolytic agents in a controlled fashion. The embolism protectiondevices described herein generally comprise one or more polymers withgenerally at least one polymer being an expandable polymer, e.g.,swelling, shape adjusting and/or compressed, upon release in a vessel ina patient's body. Various suitable polymers can be used for swellingincluding, for example, highly absorbing hydrophilic polymers (e.g.,polyether-polyurethane) or hydrogels, while shape adjusting polymers canbe memory polymers as described below. Compressed polymers arephysically deformable or elastic such that they can be squeezed into asheath or the like for delivery into a vessel of the patient, such thatthe polymer expands following removal from the sheath. In someembodiments, the device comprises a plurality of polymers in a blendand/or a plurality of monomers in a copolymer, which can be a blockcopolymer. An advantage of using a plurality of polymers includes, forexample, the ability to introduce properties characteristic of eachindividual polymer or of each monomer group incorporated into acopolymer.

In general, the expansion of the polymer and the corresponding devicecan occur spontaneously following the application of an appropriatestimulus. The appropriate stimulus can be, for example, contact with anaqueous fluid, release of constraining forces, such as applied by asheath, and/or heating to body temperature. The expandable nature of atleast some of the materials of the embolism protection devicesinherently allows them to conform to the patient's vessel. Thus, minorvariation in the vessel size and shape along the extent of the devicecan be handled appropriately by minor variations in the expansion of thedevice at different locations. However, for vessel or branch points ofvessels that have a more complex non-cylindrical structure, the deviceshape can be formed specifically to adjust for delivery at theparticular shape of the vessel. In these embodiments, the device expandsinto a predictable non-cylindrical shape due to the pre-shaping of thedevice.

Suitable swelling polymers can include, for example, hydrogels andsponge materials. The amount of swelling that takes place upon contactwith an aqueous medium can range from about 10 percent to greater than afactor of twenty times (i.e. 2000 percent), in some embodiments from afactor of fifty percent to a factor of fifteen times, in otherembodiments from a factor of two times to a factor of twelve times, andin further embodiments from a factor of seven times to a factor of tentimes. A person of ordinary skill in the art will recognize thataddition ranges of swelling within the explicit ranges are contemplatedand are within the present disclosure. The desired degree of swellingmay be selected to provide the desired degree of pressure between thedevice and the vessel wall following deployment as well as accountingfor the relative sizes of the vessel and the delivery device, such as acatheter. The device may further be compressible apart from theexpansion from hydration such that release of the device from thedelivery system results in an expanded device relative to itspre-delivery size. However, generally some swelling or other expansionis used to maintain the device within the vessel in which the swellingprovides pressure against the vessel wall. Generally, the devicecontacts the wall over a significant portion of its outer surface suchthat the force against the vessel is distributed over a significantarea. Since the force generally is spread over a significant area, themagnitude of the force can be correspondingly reduced such that there isless potential for damage to the vessel wall. Furthermore, as describedabove, the embolism protection device can be tethered in place such thatlittle or no force is needed between the device and the vessel wall tohold the device at the delivered position.

Hydrogels are hydrophylic polymers that generally are crosslinked tomake them insoluble in an aqueous solution. Due to the hydrophylicnature of the polymer functional groups, the hydrogels draw aqueoussolution into the polymer material. Suitable hydrogels include, forexample, crosslinked forms of polyacrylamide,poly(hydroxyethylmethacrylate) (PHEMA), cellulose derivatives,poly(vinyl alcohol) and polyethylene glycol. The degree of crosslinking,composition and other features can be used to control the degree ofswelling. Some hydrogels can swell by a factor of 1000 percent or moreupon contact with an aqueous solution. Several qualities of hydrogelshave made them an attractive option in the medical device arena. Thesequalities include their ability to work as a protective barrier for openwounds and absorb excess fluids. In addition, hydrogels arebiocompatible, nontoxic, and nonthrombogenic, have inherent adhesivenessto tissue and have been shown to deliver drugs in a controlled fashion.(15) Also, the hydrogels can be used to associate with other polymersthat are less biocompatible or more thrombogenic to introduce desirableproperties to the composite.

Suitable foam and sponge materials include, for example, polyester,aromatic vinyl polymers, polyether, polyurethane and mixtures thereof.Modified polyurethane polymers can be used to improve thebiocomatability of the polymer. See, for example, U.S. Pat. No.6,320,011 to Levy et al., entitled “Derivatized PolyurethaneCompositions Which Exhibit Enhanced Stability In Biological Systems AndMethods Of Making The Same,” incorporated herein by reference. Thefoam/sponge materials can be formed, for example, in a molding processwith a blowing agent. An example of a polymeric sponge material andmethods of forming the sponge material are described further in U.S.Pat. No. 4,456,706 to Siedenstrang et al., entitled “Molding compounds,Sponge Articles Produced Therefrom And Process Of Production,”incorporated herein by reference.

Compressible biocompatible polymers include, for example, foam productsuseful for biological applications. For example, hydrophilicpolyether-polyurethanes and polycarboxylate polyurethanes can be used toform foam that are compressible while absorbing a large amount ofaqueous solutions. U.S. Pat. No. 5,914,125 to Andrews et al., entitled“Wound Dressing,” incorporated herein by reference, describes ahydrophilic polyether polyurethane foam material with an adsorptivecapacity of at least about 10 times its own weight. In addition,published U.S. patent application Ser. No. 2002/0072550A to Brady etal., entitled “Biostable Polyurethane Products,” incorporated herein byreference, describes foam materials with a void volume of 85% that areformed from either polyether polyurethanes or polycarbonatepolyurethanes. In addition, polyurethanes poly-vinyl polymers can alsobe used to form biocompatible foams. U.S. Pat. No. 4,550,126 to Lorenzet al., entitled “Hydrophilic, Flexible, Open CellPolyurethane-poly(N-vinyl lactam) Interpolymer Foam And Dental AndBiomedical Products Fabricated Therefrom,” incorporated herein byreference, describes a foam with a good ability to absorb aqueousfluids. These foams can be formed into appropriate shapes for use in theembolism protection devices described herein.

In some embodiments, the embolism protection device can comprise apolymer blend and/or copolymer as other polymers alone may not provideall desired functions or properties. Specifically, it may be desirableto use at least one polymer to provide additional mechanical strength tothe device within the flow and an expanding polymer, such as a hydrogel,to introduce the expansion of the device upon delivery and to providefor control of the porosity of the expanded device. Suitable structural,biocompatible polymers for these blends include, for example,polyesters, such as polyethylene terephthalate, and polyurethanes, suchas polycarbonate-polyurethanes, polyether polyurethanes,silicon-polyether-urethanes and silicon-polycarbonate-urethanes. Forembodiments in which the expansion involves a swelling polymer, thesepolymer blends comprises from about 25 weight percent to about 95 weightpercent structural polymer relative to the total polymer of the blends,and in further embodiments from about 35 to about 85 weight percentstructural polymer relative to the total polymer of the blends. Inembodiments in which expansion involves a shape changing polymer and/ora compresses polymer, a polymer blend generally would comprise at leastabout 40 weight percent expanding polymer and in other embodiments atleast about 50 weight percent expanding polymer. Similarly, theproportions can be considered with respect to the weight of blocks of ablock copolymer. A person of ordinary skill in the art will recognizethat additional ranges of structural polymer proportions within theexplicit ranges are contemplated and are within the present disclosure.

In some embodiments, the embolism protection device can comprise abiodegradable shape adjusting or memory polymer. These polymer cantransition to a memory shape upon application of a stimulus, such as atemperature change. In particular, biodegradable polymers are availablethat resume a memory shape upon placement at body temperature or pH. Thememory shape can be an expanded form that would extend the device acrossthe lumen of the vessel. Thus, the memory polymer can expand theembolism protection device without the assistance of a swelling polymer,although the device may or may not comprise a blend or copolymer withthe memory polymer and a hydrogel or other swelling polymer. Suitablememory polymers are described further in U.S. Pat. No. 6,160,084 toLanger et al., entitled “Biodegradable Shape Memory Polymers,”incorporated herein by reference. These polymers, in particular, can beused to form devices with a saddle shape, as shown in FIGS. 5A and 5B.In some embodiments, the device with a biodegradable polymer can becombined with an initial amount of tPA and vectors to deliver anexpressible tPA gene to transfect nearby cell to supply tPA on a longerterm basis after the initial tPA with the device has eluted. Thedegradation of the device avoids the need to eventually remove thedevice and the supplies of tPA dissolve emboli such that the device doesnot become clogged with emboli during a more extensive implantation.

Other suitable memory polymers include, for example, hydrophilic polymerfibers, including, for example, polyester fibers. Suitable fibers aredescribed, for example, in U.S. Pat. No. 5,200,248 to Thompson et al.,entitled “Open Capillary Channel Structures, Improved Process For MakingChannel Structures And Extrusion Die For Use Therein,” incorporatedherein by reference. The capillary channel structures described inThompson are collapse-resistant, and the capillary channel of thestructures of Thompson are open along a substantial length in the axialdirection of the structure such that fluid can be received from outsideof the channel as a result of such open construction. These fibers canbe heated gently to cause the fibers to curl. The curled fibers can bestretched straight at room temperature. Upon heating to bodytemperature, the fibers resume the curled configuration. By using abundle of the stretched fibers, the individual fibers of the bundle curlupon delivery due to body heat/hydration to form a fibrous filter matthat can entrap emboli within the fibrous network. The appropriatenumber of fibers for the bundle can be selected empirically to yield thedesired packing density in the resulting mat and corresponding effectivepore size.

One means of creating copolymers with desired properties is to form agraft copolymer. A graft copolymer is prepared by linking together twodifferent polymers, for example, by way of chemical initiation (10) orradiation (11) in the form of ultra violet light, gamma or x-rayirradiation. A graft copolymer can exhibit properties closely related tothe two parent compounds. Some copolymer embodiments harbor the tensilestrength and biostability of polyethylene terephthalate and the superabsorbent swelling of polyacrylamide.

Polyethylene terephthalate (PET) polyester has been used extensively inmedical devices including sutures and large diameter vascular graftswith good clinical success. (12) The molecular formula for PET isH—[O—(CH₂)₂—O—CO—(C₆H₄)—CO]_(n)—R where R can be, for example, OH(Dacron®) or OCH₃ (terylene), and the chemistry and fiber manufacture iswell worked out. The FDA has approved PET for such implants as fabricused in suture (temporary implant) or sewing rings for heart valves(permanent implant). (13) Given these characteristics, PET is suitableas the base material for an embolism protection device.

Polyacrylamide belongs to the class of hydrogels known as superabsorbent polymers. These polymers swell in the presence of aqueoussolutions and can increase to 1000 times their original size. (14) Theability of polyacrylamide to swell can contribute significantly to theefficacy of some embodiments of the device design proposed here.However, placing such a material in the vasculature involves appropriatecontrol of swelling parameters to avoid vessel harm from excessiveswelling. In addition, swelling can cause changes in polymer porosity.(30) A pore size that is too small may hinder blood cell flow, while apore size that is too large may allow emboli to pass. The design of thedevice contributes significantly to porosity, however porosityassociated with swelling can also contribute to the function ofentrapping emboli.

The desirability of polyacrylamide as a material for the devicesdescribed herein stems at least in part from its chemical structure.Polyacrylamide is derived from acrylamide monomer units. The molecularformula is —[CH₂CHCONH₂—]_(n)—. Polyacrylamide is a linear hydrogelwhich can react with many kinds of compounds to produce derivatives ofpolyacrylamide with many valuable properties such as flocculation,thickening and surface activity. (16, 29) This reactivity allows foraddition of functional groups, which may alter its physical properties.In addition, there is a group of special polyacrylamide copolymerscalled super absorbent polymers. (17, 21) These polymer can absorb waterten to one-thousand fold of their original weight and, under certainpressure, do not dehydrate. During expansion, super absorbent polymersare capable of delivering agents to the surrounding microenvironment,which is a quality useful for delivery of thrombolytic agents fromcorresponding devices. Super absorbent hydrogels are also furtherdescribed in U.S. Pat. No. 6,271,278 to Kinam et al., entitled “HydrogelComposites And Super Porous Hydrogel Composites Having Fast Swelling,High Mechanical Strength, And Superabsorbent Properties,” incorporatedherein by reference. As with PET polyester, polyacrylamide is approvedby the FDA for use in medical adhesives. (18) The FDA approval of thematerial together with its material properties makes polyacrylamide asuitable polymer and/or copolymer for use in the embolism protectiondevices described herein. Polyacrylamide has been used as a controlledrelease vehicle for anti-microbial agents. (28)

Extensive studies have been conducted on the swelling and deswelling ofpolyacrylamide. (26) Several factors contribute to the swellingproperties of polyacrylamide including swelling agent composition,curing time, degree of hydrolysis, temperature and cross-linking.Cross-linking is most intimately tied to swelling, for swelling isdescribed as the process necessary to attain equilibrium betweenthermodynamic expansion (Flory-Huggins theory, 1953) and the retractiveforce of the cross-linked structure. There are several means to altercross-link degree and formation including alteration of preparationphysical state (dry vs. wet), cross-linking duration, and cross-linkingagent. A recent study investigated the effect of several differentcross-linking agents on polyacrylamide gel swelling. (27) In brief, a5×5 cm piece of polyacrylamide gel was dehydrated and weighed. Thesample was then immersed in 100 ml of distilled water, and the weight ofthe samples was taken at 10 minute intervals. The weight degree ofswelling, q, (ratio of the weight of the swollen sample to that of thedry sample) was plotted as a function of time. Results indicate agreater than six-fold change in weight degree of swelling simply byaltering the cross-linking agent. Control of polyacrylamide hydrogelporosity and crosslinked density is described further in U.S. Pat. No.6,391,937 to Beuhler et al., entitled “Polyacrylamide Hydrogels AndHydrogel Arrays Made From Polyacrylamide Reactive Prepolymers,”incorporated herein by reference. By varying the crosslinking agent,prepolymer properties and the degree of crosslinking, the porosity ofthe hydrogel can be controlled to satisfy desired device parameters.

In some embodiments, block copolymers can be used to introduce a stableform of a polymer blend in which the hydrogel is bonded to a structuralpolymer. In particular, the hydrogel can be grafted onto the structuralpolymer material based on knowledge in the art. In particular, polymericmaterials have been grafted together using plasma, although othercrosslinking approaches can similarly be used. A high-energy plasmatechnique generates active groups in the polymer, which facilitate thegrafting of the second substrate to the first. The chemical compositionof the two materials are complementary to this potential bonding andhave been individually used to generate graft copolymers. (24) Thiscopolymer matrix has the potential to swell and develop significantporosity in a controllable fashion. This reaction results in thegrafting of polyacrylamide onto the (PET) fibers. This grafting can befurther or alternatively facilitated with ultraviolet crosslinking. (25)(See Equation 1.)

Reaction of Polyacrylamide and PET Polyester

In some embodiments, the embolism protection device comprises abiodegradable/bioresorbable polymers. These embodiments may or may notfurther comprise a biologically active agent that is released by thedegradation of the biodegradable polymer following implantation within apatient. Suitable biodegradable polymers include, for example,polysaccharides, such as polydextran, cellulose and starch, hydroxyethylstarch, derivatives of gelatin, polyvinylpyrrolidone, polyvinyl alcohol,poly[N-(2-hydroxypropyl)methacrylamide], poly(hydroxyacids),poly(epsilon-caprolactone), polylactic acid, polyglycolic acid,poly(dimethyl glycolic acid), poly(hydroxybutyrate), copolymers thereofand mixtures thereof.

To form the desired structures from the polymers, the polymers duringthe crosslinking/grafting step can be molded into the desired form.Various molding techniques can be used, such as injection molding,casting, compression molding and the like. However, other polymerprocessing approaches can similarly be used, such as extrusion,calendering, blowing and the like. In particular, foam materials can beformed conveniently by extrusion, and composite materials can be formedby coextrusion. In some embodiments, the porosity is introduced througha particulate pore forming agent that is combined with the polymerduring processing and subsequently removed, such as by dissolving theparticles while leaving the polymer intact, to leave the pores. Thenature of the porosity is determines in part from the nature of the poreforming materials. If sponge-like materials are formed by foaming,non-uniform pressure can be applied to the expanding foam to change theresultant porosity.

Additional materials, such as metals, can be introduced into the polymerto render the device radio-opaque such that it can be visualized viaangiography or clinical techniques. Biocompatible metals include, forexample, titanium, titanium-nickel alloys, and stainless steel.Guidewires, tethers and the like can also be formed from thesebiocompatible metals and/or biocompatible fibers, which can be formedfrom the same materials as the biocompatible fabrics described below.Also, the embolism protection device can further comprise abiocompatible adhesive, especially on the exterior of the device tofacilitate anchoring of the device at the place of delivery. Suitablebiocompatible adhesives include, for example, commercially availablesurgical adhesives, such as cyanoacralate (such as 2-octyl cyanoacrylatefrom Ethicon Products), fibrin glue (such as Tissucol® from Baxter) andmixtures thereof.

Also, the exterior can be covered with a biocompatible fabric.Biocompatible fabrics can be formed from a variety of materials, such assilk, nylon and/or polyesters, including, for example, Dacron®polyester. The fabric can be selected to have a porosity smaller thanthe porosity of at least a portion of the remaining device or noporosity, such that trapped emboli generally do not pass through thefabric upon the removal of the device from the patient. Similarly, theembolism protection device can have a coating, such as a polymercoating, which can be formed by stray coating or dip coating a polymersolution or a polymer melt, which forms the polymer coating upon dryingor cooling, respectively. Such a polymer coating may not be inherentlyporous, and desired porosity can be introduced by mechanicallypuncturing the coating with a fine needle or the like or by laserdrilling appropriate pores. A wide variety of lasers with moderate powercan be used for the drilling and conventional optics can be used tofocus the laser beam to produce the desired pore size.

Bioactive Agents

The embolism protection devices alone provide control over the movementsof emboli within the patient's vessel. However, it may be desirable tocombine the mechanical features of the device with biologically activeagents to provide another dimension to the treatment. The association ofbioactive agents with the device can both provide treatment to shrink oreliminate emboli within the device and/or also to deliver a bioactiveagent downstream from the device. Suitable bioactive agents include, forexample, thrombolytic (anti-thrombogenic) agents, anti-platelet agents,anti-coagulation agents, growth factors and combinations thereof.

Suitable thrombolytic agents include, for example, tissue-typeplasminogen activator (tPA), mutated forms of tPA, such as TNK-tPA andYM866, urokinase, streptokinase, staphylokinase, and the like. Inparticular, tPA is a polypeptide that acts upon plasminogen to formplasmin. Plasmin breaks down fibrin, one of the main structural proteinsin blood clots. (22, 23) Plasmin also lyses fibrinogen, a precursor offibrin. tPA can be produced according to the method described in U.S.Pat. No. 4,935,368 to Ryotaro et al., entitled “Process For ProducingTissue Plasminogen Activator,” incorporated herein by reference. Aneffective precursor of tPA is described in U.S. Pat. No. 6,001,355 toDowdle, entitled “Pro-tPA For The Treatment Of Thrombosis, Embolism AndRelated Conditions,” incorporated herein by reference. Analogs, i.e.mutated forms, of tPA are known, for example, as are described in U.S.Pat. No. 5,106,741 to Marotti et al., entitled “Tissue PlasminogenActivator (TPA) Analogs,” published PCT application WO 93/20194 to Satoet al., entitled “TPA Analog,” and PCT published application WO 02/22832to Xia et al., entitled “A Cell Line Expressing Mutated HumanTissue-Type Plasminogen Activator, The Constructing Strategy Thereof AndMethods Of Preparing Expressed Protein,” all three of which areincorporated herein by reference. Elsewhere in this applicationincluding the claims, tPA refers to natural tPA, fragments thereof andanalogs thereof that are effective to stimulate the formation ofplasmin.

Together with a sound materials design, an embolism protection deviceassociated with tPA can be capable of destroying emboli associated withcardiopulmonary bypass. Recent reports suggest that most of the emboligenerated during cardiopulmonary bypass have a significant fibrincomponent. (19, 20) The body's primary means of degrading fibrin is viatissue plasminogen activator (tPA). tPA is currently in clinical use asa remedy for heart attack and stroke (thrombolysis, reperfusiontherapy). This therapy involves delivering tPA through an intravenousline to break up and dissolve a clots in the coronary artery, therebyrestoring blood flow. (21) tPA is of particular interest for use withembolism protection devices described herein given its high specificityfor clot degradation without causing systemic bleeding events.

Suitable anti-platelet agents include, for example, acetylsalicylicacid, ADP inhibitors, phosphodiesterase III inhibitors, glycoproteinIIB/IIIA inhibitors, adenosine reuptake inhibitors, nitrates, such asnitroglicerin and isosorbide dinitrate, and Vitamin E. Suitableanti-coagulation agents include, for example, heparin, warfarin, and thelike. Suitable growth factors include, for example, vascular endothelialgrowth factor (VEGF) and the like.

In some embodiments, materials are incorporated into the device thatform by decomposition a therapeutic composition. For example, nitricoxide (NO) can stimulate beneficial vascular responses. Compounds withan NONO⁻ functional group can emit nitric oxide following implantationof the medical device. Suitable compositions include, for example,(CH₃)₂CHNHNONO⁻, (CH₃CH₂)₂NNONO⁻, H₂N(CH₂)₃ NHNONO⁻, NaNONONa. Thesynthesis of 1-(2S-carboxypyrrolidin-1-yl)-oxo-2-hydroxydiazene disodiumsalt, 1-hydroxy-2-oxo-3-carboxymethyl-3-methyl-1-triazine N-methylamidedisodium salt, 1-hydroxy-2-oxo-3-carboxymethyl-3-methyl-1-triazineN-methylamide sodium salt, the bis(nitric oxide) adduct ofL-prolyl-L-leucylglycinamide, and corresponding protein adducts aredescribed in U.S. Pat. No. 5,632,981 to Saavedra et al., entitled“Biopolymer-Bound Nitric Oxide Releasing Compositions, PharmaceuticalCompositions Incorporating Same And Methods Of Treating BiologicalDisorders Using Same,” incorporated herein by reference. Conjugates ofheparain, for example with dermatan sulfate, that are effective toprevent thrombosis are described in U.S. Pat. No. 6,491,965 to Berry etal., entitled “Medical Device Comprising Glucosaminoglycan-AntithrombinIII/Heparin Cofactor II Conjugates,” incorporated herein by reference.Furthermore, some polymers decompose to form an acidic moiety, such aspolyhydroxybutyrate degrading to 3-hydroxyvaleric acid.

The bioactive agent can be associated with the materials of the embolismprotection device by one or more approaches. For example, the device canbe contacted with a solution of the agent such that the agent can beinfused within the device. The agent is then released, possiblygradually, upon implantation of the device. For example, duringexpansion, super absorbent polymers can be capable of delivering agentsto the surrounding microenvironment, a quality appropriate for deliveryof thrombolytic agents or other bioactive agents. In other embodiments,the bioactive agents are placed in contact with the polymers during thepolymerization and/or crosslinking/grafting steps such that thebioactive agents are incorporated within the polymer matrix. Thebioactive agents then elute following implantation.

For systemic administration, the therapeutic dose of tPA for a humanpatient can be 0.01 to 80 micro moles (70-8750 ng/ml) but is thought tobe most effective at 500-1000 ng/ml. (31) Lower doses may be effectivewith local delivery since the local concentration can be higher over thedelivery period. An appropriate corresponding dose for local deliverycan be sustained throughout the time of implant. If the dose is releasedtoo quickly, a toxic environment can ensue (>25,000 ng/ml for systemicdelivery). (32) To determine the initial loading dose, the releasekinetics of tPA from the device can be used to deliver a desired dose oftPA or other biologically active agent. An empirical evaluation of anappropriate dose can be estimated from in vitro studies, such as theflow loop studies described below, or in animal studies. In someembodiments, it may be desirable to deliver the biologically activeagent with a suitable biocompatible carrier. Suitable biocompatiblecarriers can be, for example, a physiologically buffered saline.Suitable buffers can be based on, for example, the following compounds:phosphate, borate, bicarbonate, carbonate, cacodylate, citrate, andother organic buffers such as tris(hydroxymethyl)aminomethane (TRIS),N-(2-hydroxyethyl) piparazine-N′-(2-ethanesulfonic acid) (HEPES) ormorpholine propanesulphonic acid (MOPS). The ionic strength of thebiocompatible carrier can be adjusted by the addition of one or moreinert salts including, for example, NaCl, KCl and combinations thereof.Preferably, the ionic strength is near physiological values.

Additionally or alternatively, genes coding for desiredpolypeptide-bioactive agents can be delivered in a vector. The vectorcan be taken up by adjacent cells and expressed as the protein. Suitablevectors are known in the art, and include, for example, viral vectors,plasmids and the like. In particular, a vector encoding tPA can bedelivered through the device. The effectiveness of a vector for tPAexpression in rabbits is described further in Waugh et al., “Genetherapy to promote thromboresistance: Local over-expression of tissueplasminogen activator to prevent arterial thrombosis in an in vivorabbit model, Proceeding of the National Academy of Sciences—USA 96(3):1065-1070 (Feb. 2, 1999), incorporated herein by reference. Vectors, forexample, plasmids and viral vectors, suitable for transforming humancells with appropriate control sequences for expression in human cellsare described further in U.S. Pat. No. 5,106,741 to Marotti et al.,entitled “Tissue Plasminogen Activator (TPA) Analogs,” and U.S. Pat. No.4,935,368 to Ryotaro et al., entitled “Process For Producing TissuePlasminogen Activator,” both of which are incorporated herein byreference.

Use Of the Embolism Protection Device

Nearly all cardiac surgical procedures and well as certain non-cardiacprocedures and natural events, such as kidney stone formation, result inthe generation of emboli, in the broad sense used herein. Emboligeneration frequently causes life altering, and possibly lifethreatening neurological disturbances. The emboli protection devicedescribed herein can be useful for all patients undergoing cardiacsurgery and for other procedures. In some embodiments, the elegantdesign employs a unique combination of FDA approved materials andtherapeutic agents to provide an easy to use and effective means ofcontrolling embolic events. At some point following the delivery of anembolism protection device, it may be desirable to remove the device ora portion thereof.

In general, embolism protection devices can be supplied to medicalprofessionals in a range of sizes, such that an appropriate size can beselected from the available sizes for a particular patient and for aparticular point of placement. Due to the expanding nature of theembolism protection device a precise size device is not required sincethe device conforms over a reasonable range to the vessel. Nevertheless,imaging techniques and estimates from experience and the patient's sizecan provide an appropriate estimate for the appropriate size of theembolism protection device. An embolism protection device can be placedwithin the desired vessel of a patient with a catheter, a syringe, aguidewire or the like. In particular, an embolism protection device canbe attached to a guidewire to feed the device through a catheter to adesired position in a vessel within a patient. The guidewire can beseparate from the device following the placement of the device, or theguidewire can remain tethered to the device to facilitate maintainingthe device at the desired position and/or to facilitate removal of thedevice. Removal of the guidewire can be performed by pulling out theguidewire if the guidewire is not attached to the device and if thedevice is applying sufficient force against the walls of the vessel suchthat friction can hold the device in place. If the guidewire is toremain attached to the device, the guidewire can be attached to thedevice with a mechanical attachment or with an adhesive. The guidewirecan be mechanically attached to the device, for example, by forming thepolymer around the end of the wire, generally with a non-straightsection of wire, winding the wire around a section of the device and/orheat strinking a portion of the polymer around the end of the wire.

Due to the potentially serious outcomes of cardiac intervention that canresult in emboli associated with the aorta, the embolism protectiondevice can be positioned at one or more positions within the aorta or inarteries branching from the aorta. Referring to FIG. 12, aorta 200 isshown adjacent heart 202. As shown in FIG. 12, five embolism protectiondevices 204, 206, 208, 210, 212 are shown in different positions. Anyone or more of these can be used for a particular patient. Devices204-212 are shown with device 204 in the ascending aorta, device 206 inthe descending aorta, device 208 in the innominate artery, device 210 inthe left common carotenoid artery and device 212 in the left subclavianartery.

Referring to FIG. 13, an embodiment is shown that is appropriate for usewhen the heart is on bypass. In particular, this device can be placed inthe aorta distal to the site of cross clamp in a cardiac surgicalprocedure involving cardiopulmonary bypass. In this embodiment, anembolism protection device 220 is within the ascending aorta 222 distalto cross clamp 224 and is attached to an aortic cannula 226, forexample, with a fastener 228, such as a loop of material, a clip,anchor, a catching device or the like. An aortic cannula generally canbe used to return blood to the heart when the heart is on bypass. Forexample, the heart can be placed on bypass during a procedure to repairportions of the heart. Aortic cannula are known in the art, and oneembodiment is described in U.S. Pat. No. 6,387,087 to Grooters, entitled“Aortic Cannula,” incorporated herein by reference. Attachment to aorticcannula 226 stabilizes device 220 at the pressures experienced duringthe cross clamp procedure. Referring to FIG. 14, release of cross clamp224 can result in the corresponding release of emboli 230 that aretrapped by embolism protection device 220. Device 220 can releasebioactive agents to dissolve emboli 230, and, additionally oralternatively, removal of device 220 can remove trapped emboli. Forexample, device 220 can be removed from the cannula site shortlyfollowing the removal of the cannula.

In some embodiments, an embolism protection device can be placed withina coronary artery. In particular, the embolism protection device can beplaced down stream from a planned site of intervention, for example, byangioplasty, placement of a bypass graft or introduction of a stent.Referring to FIG. 15, embolism protection device 240 is shown withincoronary artery 242 of heart 244. Device 240 is located downstream inthe artery from an intervention site 246.

In other embodiments, an embolism protection device can be place in thevenous side of the heart/vascular system to prevent emboli to the lungs.Referring to FIG. 16, embolism protection device 250 is within thepulmonary artery 252 downstream from the pulmonary heart valve 254 wherepulmonary artery 252 attached to heart 256. Flow from the pulmonaryartery goes to the lungs. More generally, an embolism protection devicecan be placed within any vessel in the body. As shown in FIG. 17,devices 260, 262 are within arteries leading to the leg from thedescending abdominal aorta 264 while device 266 is in an arm. Embolismprotection devices can be similarly placed in veins.

As noted above with respect to FIG. 12, the embolism protection devicecan comprise two distinct portions or similarly can be used with aseparate but associated drug delivery article. Use of such devices inthe context of the application of a stent is shown in FIGS. 18A, 18B and18C. As shown in FIG. 18A (left), a two component embolism protectiondevice 270 is placed downstream from a plaque deposit 272 in vessel 274.In this embodiment, device 270 comprises a tether 276 to facilitateremoval, although other removal approaches can be used. FIG. 18A (right)is a schematic enlarged view of a cross section of a surface capillaryfiber showing one or more grooves 271 on the surface of the fiber of theembolism protection device 270. As shown in FIG. 18B, a stent 278 hasbeen applied to plaque deposit 272 with the potential generation ofemboli 280, which are trapped by embolism protection device 270. Asshown in FIG. 18C, an embolism trapping portion 282 of device 270 isbeing removed using tether 276, while a bioactive agent eluting portion284 of device 270 remains in vessel 274.

The elution of a bioactive agent from the embolism protection device isdescribed above. Additionally or alternatively, one or more bioactiveagents can be delivered through a guidewire or the like tethered to theembolism protection device. The guidewire can have a small inner channelthat has an opening into the vessel at or near the proximal end. Theflow rate and time determines the dose of biologically active agentdelivered into the vessel. Referring to FIG. 19, embolism protectiondevice 300 associated with guidewire 302 is within a body vessel 304.Guidewire 302 has a small internal channel that can have an opening atpoint A, B and/or C. The natural flow direction in the vessel isindicated by arrow 306. Delivery of a biologically active agent at pointA results in the flow of the agent through device 300 and downstream.Delivery of the agent at point B results in a concentration of the agentwithin the device with any residual agent flowing downstream. Inaddition, delivery of the agent at point C results in delivery of theagent downstream from the device.

Once the embolism protection device has served its purpose, it may bedesirable to remove the device or a portion thereof. For example,shortly after completing a procedure, the device may have had theopportunity to collect and/or dissolve the emboli of significance.Alternatively, once the embolism protection device has completed elutinga biologically active agent following the trapping and/or dissolving ofemboli associated with a procedure or other event, it may be desirableto remove the device. Removal of the device can take place, for example,minutes, hours, days, months or years following delivery depending onthe particular device and its intended purpose.

As noted above, in some embodiments, an embolism protection device canbe attached to one or more tethers or the like such that pulling on thetethers tends to reduce the size of the device such that it can be movedupstream from its delivered position. In other embodiments, an embolismprotection device can have a reduced diameter or pointed tip at theproximal end. With a reduced diameter proximal end and a compressiblepolymer structure generally possessed by the device, the device can bepulled within a sheath using a tether due to the forces applied to thedevice at the end of the sheath. Once the device is confined within thesheath, the device can be withdrawn from the vessel with the sheath.

In alternative or additional embodiments, an extraction device can beused to facilitate removal of the embolism protection device. Anextraction device comprises a gripper that can grip the embolismprotection device and reduce the diameter of at least a portion thereof.The gripper can be positioned within the vessel through a catheter orthe like. An actuating wire or other control device can connect thegripper with a control handle at the proximal end of the gripper deviceoutside of the patient. Thus, the gripper can be manipulated by a healthcare professional from outside of the patient using appropriatevisualization techniques, such as a fiber optic based visualizationsystems for minimally invasive surgical procedures.

An embodiment of a suitable gripper is shown in FIG. 20. Gripper 310 hasa gripping portion with four flexible arms 312 extending from a shaft314. Shaft 314 can have a hollow core for threading the shaft over aguide-wire or the like. An outer shaft 316 can move in position relativeto shaft 314. Outer shaft 316 can engage arms 312 and deflect themtoward the center of shaft 314. This deflection of arms 312 results in agripping function. Thus, if arms 312 are positioned along the outersurface of an embolism protection device, the deflection of arms 312toward a center axis compresses the embolism protection devicecorrespondingly. This deflection can be continued until the gripper andthe embolism protection device has a small enough profile for removalfrom the vessel. For embodiments of an embolism protection device with aplurality of sections, gripper 310 can be used to facilitate removal ofa portion of the embolism protection device oriented toward the gripper.Furthermore, various other gripper configurations, including, forexample, some configurations developed for use with catheters for otherfunctions can be adapted for use in removing an embolism protectiondevice.

EXAMPLES Example 1 Synthesis of Hydrogel Grafted Polymer

This example demonstrates the synthesis of a polyacrylamide hydrogelpolymer grafted onto a PET polyester polymer.

Medical grade PET fibers were surface activated by subjecting them to anoxygen plasma. The plasma glow discharge system primarily consisted of abarrel radio frequency (RF) plasma reactor with a diameter and depth ofsix inches (Extended Plasma Cleaner, Harrick Scientific, Ossining,N.Y.). The pressure was monitored by a thermocouple vacuum gauge(Hastings Vacuum Gauge, DV-6). The reaction chamber was evacuated to 10millitorr (mtorr) to remove contaminants and moisture. The chamber wasthen flooded with research grade oxygen gas (99.99%), and evacuateduntil a constant pressure of 150 mtorr was established, at which pointRF plasma of 30 Watt was applied for ten minutes. Activated fibers werethen dip coated with a mixture of polyacrylamide (10% by weight (wt)),acrylamide monomer (10%-20% by wt), and methylenebis-acrylamide(0.05-0.1% by wt crosslinker) and a UV sensitive initiator in water. Thegrafting was allowed to cure under a UV lamp for 10 minutes.

Visual inspection and microscopic techniques verified matrix synthesis.See FIGS. 21 and 22. The grafted copolymer matrix was then characterizedusing swelling control studies.

Example 2 Incorporation of Biological Agent into Hydrogel and ControlledRelease

This example demonstrates the incorporation of tPA into a polyacrylamide(PAM) polymer and the subsequent release of the tPA.

In this experiment, tPA was incorporated into a polyacrylamide hydrogelby dispersion into the polymerization solution at the time ofpolymerization. This method may result in the entrapment of the tPA inthe interstices of the gel-like matrix where it is held until hydrationat which time the agent is slowly released.

A 2.8 ml solution was prepared comprising 1.5 ml-5 weight % acrylamidesolution (approximate final concentration based on a volume per volumedilution 2.67% acrylamide), 6 μl-human two-chain tPA (2.2 mg/ml, fromMolecular Sciences, MI), 9 μl-10% ammonium persulfate, 2.25 μl-TEMED(N,N,N′,N′-tetramethylenediamine, 99% solution) and deionized water. Theammonium persulfate produces free radicals faster in the presence ofTEMED such that the addition of TEMED to the mixture accelerates thepolymerization and crosslinking of the gel. Three aliquots of 500 μlgels were made in glass test tubes and allowed to polymerize for 1 hr atroom temperature (total tPA conc. 4.4 micromolar μM in each gel), thuscreating three gels. Upon onset of polymerization, 50 μl of the controlsamples were removed and kept at −80° C.

The release kinetics of the tPA was analyzed. After polymerization, thegels were carefully removed from the test tubes and put in 20 ml vials.The test tube was rinsed with 5 ml of phosphate buffered saline (PBS),and the rinse poured over the gel in the 20 ml vial. This was slightlyshaken to rinse the gel and to remove any unincorporated tPA. A 50 μlquantity of this solution was frozen. The remainder was poured off andreplaced with another 5 ml of PBS. Both the gels and the controls werekept at 4° C. for the release experiment in an effort to prevent proteindegradation and slightly shaken on an oscillating shaker. At designatedtime points, 50 microliter (μl) aliquots of buffer were taken. Theamount of tPA in each aliquot was determined via ELISA (Diapharma Group,Inc. Westchester, Ohio). In brief, buffer samples were transferred in100 μl volumes to wells of a 96-well plate containing anti-tPA IgG. Thesamples were incubated for 2 hours at room temperature. Bound tPA wasdetected with HRP (horseradish peroxidase)—labeled Fab fragments ofanti-tPA IgG followed by a peroxidase substrate. Colorimetric stainingwas detected and actual quantity determined via comparison to theincluded standards (Biopool International, Cat#101-442).

FIG. 23 shows the standard curve for the tPA ELISA. The curve was linearover the range tested with an R-squared value of 0.978. FIG. 23 is aplot of the experimentally measured time release kinetics of tPA fromthe hydrogel. Release of tPA from the hydrogel reached a maximum releaseof 31.4 ng/ml at 60 minutes.

We have demonstrated the ability to reliably produce a PET:PAM copolymermatrix. This matrix can be produced such that swelling is rapid,sustained and reproducible. In addition, tPA can be incorporated intothe matrix. The release rate is typical of a hydrogel with an initialquick release sustained for at least 60 minutes following testinitiation. This time duration would be sufficient forpost-cardiopulmonary bypass cross-clamp embolism protection devicefiltration time, however further crosslinking alterations can be made toalter release. This release can be tailored after the toxic doseparameters and dose necessary for emboli destruction are determined.

Example 3 In Vitro Emboli Dissolution Test

This example demonstrates the effectiveness of recombinant human TissuePlasminogin Activator (tPA) as a resolving agent with respect to thedissolution of porcine thrombolytic emboli in vitro.

tPA was diluted in phosphate buffered saline at the followingconcentrations: 1,000 nanograms/milliliter (ng/ml), 500 ng/ml, 100 ng/mland 0 ng/ml. The emboli dissolution potential of each tPA solution wasmeasured by applying the tPA solution to glass slides containing emboliand then measuring the change in emboli size as a function of time. Tocreate the emboli, coagulated porcine whole blood was placed in a 5 ccsyringe. Coagulated blood was extruded from the syringe and cut touniform size (200-225 μm diameter); these uniform coagulated bloodfragments will be referred to as “emboli”. Emboli were placed on glassslides for microscopic measurement. Samples were labeled andmeasurement/descriptions were made for each embolus. Measurement wasaccomplished with a Zeiss® Microscope and Zeiss® LSM 4 software forimage acquisition. One ml quantities of tPA solution were added to thecharacterized emboli and then placed on a shaker at 20 RPM in a testingroom at 30-35° C.

Emboli size measurements were taken at various time points. Results arereported in Table 1 below.

TABLE 1 Decrease in Geometric size tPA Sample concentration # pre Post %change 0 ng/ml 1 233.0 231.0 0.86 0 ng/ml 2 215.0 229.0 6.51 0 ng/ml 3216.0 223.0 3.24 0 ng/ml average 221.3 227.7 2.86 100 ng/ml 11 222.0216.0 −2.70 100 ng/ml 12 180.0 200.0 11.11 100 ng/ml 13 176.0 173.0−1.70 100 ng/ml average 192.7 196.3 1.90 500 ng/ml 51 221.0 201.0 −9.05500 ng/ml 52 189.0 162.0 −14.29 500 ng/ml 53 221.0 190.0 −14.03 500ng/ml average 210.3 184.3 −12.36 1000 ng/ml 101 230.0 155.0 −32.61 1000ng/ml 102 228.0 150.0 −34.21 1000 ng/ml 103 177.0 146.0 −17.51 1000ng/ml average 211.7 150.3 −28.98Thus, the tPA was effective at reducing thrombus size significantamounts.

Example 4 Evaluation with an In Vitro Flow Loop

This example demonstrates the utility of an in vitro flow loop forevaluation of an embolism protection device as well as provides anevaluation of two embodiments of an embolism protection device, one withtPA and one without tPA.

The interrupted flow loop was developed to mimic the environment of anative coronary artery. The apparatus consisted of four components: acirculation unit, the embolism protection device, the blood/media, andthe emboli. The flow loop was constructed as indicated in FIG. 24. Thecirculation unit had a heated reservoir 350 holding blood and media 352,tubing 354, a pump 356, injection ports 358, 360 and a collection vessel362. Embolism protection device 364 was held in a fixture 366 withintubing 354. Flow through the system is noted in FIG. 24 with four flowarrows.

Embolism protection device 364 was formed with two sections ofstructure. The layered system for purposes of this experiment was apolymeric construct that could both release tPA and trap the embolibased on an appropriate porosity. Referring to a schematic view of apre-hydrated device 364 in FIG. 26, a first layer 380 was a nylon meshpolymer with a 70 micron pore diameter obtained from Sefar America Inc.Depew, N.Y. Layer 380 served to entrap emboli. A second layer 382 was asponge-like layer made of polyacrylamide and impregnated with tPA. Toincorporated tPA into layer 382, a solution was prepared comprising of1.5 ml-5 weight % acrylamide solution (approximately 2.67% acrylamidefinal concentration based on a volume per volume dilution), 6 μl-humansingle-chain tPA (2.2 mg/ml, Molecular Sciences, MI), 9 μl-10% ammoniumpersulfate and 6.7 μl-TEMED. Three aliquots of 0.5 ml gels were made inglass test tubes and allowed to polymerize for 1 hr at room temperature,thus creating three gels. Following polymerization, each gel had a totalTPA amount of 500 ng at a concentration of 1,000 ng/ml). The gels wereremoved from the tubes, and the nylon mesh layer was wrapped around theflat end and the sides of each gel leaving the rounded end of the gelfrom the bottom of the tube uncovered with the mesh. Each device whenplaced within the flow loop was positioned with the flat end down-streamand with the round end upstream such that emboli are trapped by the meshwithin the gel. Following contact with an aqueous solution, the gelexpands to approximately twice its volume, as is schematically shown inFIG. 27, while the nylon mesh remains essentially unchanged, although itexpands in response to the expansion of the gel. Due to the expansion ofthe gel, the pore size of the mesh may enlarge, but this enlargement wasnot directly measured.

Three two-layer embolism protection devices were constructed with tPAincorporation, and three two-layer devices were constructed without tPAincorporation using the solution described above except with no tPA. Forthese tests, a selected device 364 held by the test fixture 366.Referring to FIG. 28, test fixture 366 has two rings 368, 370 heldtogether with a joining ring 372. Edges of device 364 are grippedbetween rings 368, 370 to fix device 364 in place.

Circulation of the media was performed with a centrifugal pump capableof generating flows from 30-120 ml/min. The tubing was a vinyl polymerwith an inner diameter from 4-6 mm, similar to that of the nativearterial vessels. The experiment was accomplished in a test chamber at37° C. Injection port 358 upstream from the embolism protection devicewas used to introduce the test emboli. The medium flowing through thesystem was phosphate buffered saline. Emboli were generated by placing 1ml of pig animal blood in a syringe and allowing it to clot (see abovefor determination of emboli size). The flow loop was validated using acalibrated flowmeter.

The emboli were introduced into the flow system at a concentration ofapproximately 15 emboli/ml of buffered saline. The time line for thetesting was as follows:

-   -   0 time—introduction of device    -   1 sec.—Begin flow of media (buffered saline)    -   10 sec—Measure flow rate    -   15 sec—Inject emboli    -   30 sec—Collect aliquot #1 (of effluent, i.e. media past device.)    -   60 sec—Collect aliquot #2    -   100 sec—Collect aliquot #3    -   200 sec—Collect aliquot #4    -   300 sec—Collect aliquot #5        After about five minutes, the flow was stopped and the device        removed and photographed microscopically. The device was then        fixed for histological analysis. Aliquots of collected liquid        were analyzed for emboli. The fixed device was snap frozen,        sectioned and placed on a slide for histological analysis.        Sections were stained immunohistochemically for fibrin and        platelet markers.

As described above, six prototypes for each design (3 with tPA and 3without tPA) were loaded in the flow loop. Emboli entrapment anddissolution was evaluated in three different ways. First, flowmeasurements were made at different flow rates to determine the degreeto which the device retarded flow. Results are outlined in the followingtable.

TABLE 2 Prototype No Device Media Mesh Only Device 30 ml/min 30.3 ± 0.6 30.0 ± 1.0  28.7 ± 0.6  60 ml/min  60 ± 0.0 59.3 ± 0.6  58.3 ± 1.5  120ml/min 119.7 ± 0.6  117.3 ± 2.5  114.3 ± 2.1  (120 ml/min) #1 #2 #3Samples w/out tPA 118 116 115 tPA 117 115 112

Second, the PBS was collected. The total collected effluent was passedover a 0.22 μm filter, and the filter was analyzed via light microscopyfor presence of emboli. The effluent had no observable emboli afterpassing through any of the six devices. This demonstrated that thedevices were effective to trap the emobli without blocking the flow.

Third, a portion of the embolism protection device was frozen andparaffin embedded for histological archiving. Selected samples weresectioned and prepared for immunohistochemistry as follows. Sectionswere postfixed for 2 minutes in 100 mmol/L tris-buffered 1%paraformaldehyde containing 1 mmol/L EDTA, pH 7.2, and rinsed with threechanges of phosphate buffered saline, pH 7.2. Porcine fibrindecomposition via tPA thrombolysis was detected using murine antibodiesspecific for neotype beta-chain fibrin (Mouse Anti-Human, Cross-reactswith pig, American Diagnostica, Inc., Greenwich, Conn., Cat 350, 1:100dilution, rhodamine conjugated, monoclonal IgG-1) and CD41 plateletglycoprotein IIa/IIIb (Mouse Anti-Human, Cross-reacts with pig,DakoCytomation, Carpinteria, Calif., Cat M7057, 1:100 dilution, FITCconjugated, monoclonal IgG-1). The antibodies listed above were dilutedin phosphate buffered saline containing 5% bovine serum albumin (SigmaChemical Co.) and applied to sections for 30 minutes. Then, the sectionwas rinsed with phosphate buffered saline. All sections werecover-slipped with a 1:8 dilution of Vectashield-DAPI(4,6-diamidino-2-phenylindole) in phosphate buffered saline (VectorLaboratories) and evaluated using an epifluorescence microscope.

Stained fibrin was analyzed and scored on a scale of 1-5; 1 being fullyintact and 5 being fully dissociated (see sample FIG. 29.). FIGS. 29Aand 29B are fibrin recovered from the embolism protection devicereleasing tPA, while FIGS. 4C and 4D show fibrin at the samemagnification recovered from an embolism protection device not releasingtPA. As seen in FIGS. 29A and 29B, fibrin treated with tPA was dissolvedaway to remove significant portions of the structure and to leaverelatively large pores in comparison with the equivalent fibrin in FIGS.29C and 29D that was not treated with tPA.

The values of the scoring are given in Table 2. Results clearly showdegradation of the emboli associated with the device in the treatedgroup and intact emboli in the devices which were not prepared with thetPA. These results show that the tPA eluting from the devices waseffective to shrink the emboli.

The embodiments described above are intended to be exemplary and notlimiting. Additional embodiments are within the claims. Although thepresent invention has been described with reference to preferredembodiments, workers skilled in the art will recognize that changes maybe made in form and detail without departing from the spirit and scopeof the invention.

LITERATURE CITED All of which are Incorporated by Reference in theirEntirety as Well as for the Specific Disclosure Noted

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What is claimed is:
 1. An embolism protection device comprising adelivery tool and a plurality of fibers in a bundle comprising a polymerand having surface capillaries characterized by one or more groovesalong the length of the fibers, wherein the fibers are associated withthe delivery tool and have a deployed configuration that fills a lumenof a vessel having a diameter corresponding to that of a human vessel inthe form of a porous filtration structure forming a fibrous filter matthat blocks a substantial majority of particulates with a diameterbetween 45 microns to 200 microns while allowing passage of blood cells.2. The embolism protection device of claim 1 wherein the fibers comprisea hydrophilic polymer.
 3. The embolism protection device of claim 1wherein the fibers comprise polyester.
 4. The embolism protection deviceof claim 1 wherein the fibers comprise a bioresorbable polymer.
 5. Theembolism protection device of claim 1 wherein the fibers are within afabric.
 6. The embolism protection device of claim 1 wherein the fibersare curled.
 7. The embolism protection device of claim 1 wherein thefibers have a curled configuration at body temperature.
 8. The embolismprotection device of claim 1 wherein the fibers are grafted with asecond polymer.
 9. The embolism protection device of claim 8 wherein thesecond polymer is a hydrogel.
 10. The embolism protection device ofclaim 1 further comprising a biocompatible adhesive.
 11. A method fortrapping emboli, the method comprising placing an embolism protectiondevice of claim 1 within a patient's vessel.
 12. The method of claim 11wherein the placing of the fibers is performed with the delivery toolthat associates with the fibers.
 13. The method of claim 12 wherein thedelivery tool holds the fibers in a configuration for passage through asheath for deployment of the fibers within the vessel.
 14. The method ofclaim 12 wherein the delivery tool comprises a guidewire.
 15. The methodof claim 11 wherein the plurality of fibers of the embolism protectiondevice of claim 1 are deployed to the porous filtration structure thatfills the lumen of the vessel with an effective pore size to trap aselected range of emboli.
 16. The method of claim 11 wherein the fibersare curled at body temperature.
 17. The embolism protection device ofclaim 1 wherein the delivery tool is a guidewire.
 18. The embolismprotection device of claim 1 wherein the fibers are attached to thedelivery tool with an adhesive.